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<p>Animal models are indispensable for linking human genetic findings to disease mechanisms. Mutations in protocadherin gamma C4 (γC4), one of the 22 isoforms encoded by the protocadherin-γ (Pcdh-γ) gene cluster, cause a human neurodevelopmental syndrome with progressive microcephaly, seizures, and intellectual disability. Here, we established a γC4 mutant mouse model that exhibits motor dysfunction, seizures, reduced brain size, and increased embryonic neuronal apoptosis. Using DOMINO (Double Mutation-Induced Open Reading Frame Switch), a two-step CRISPR/Cas9-based genome-editing strategy, we also generated γC4fl-only mice that retain full-length γC4 while truncating the other 21 Pcdh-γ isoforms. Unlike Pcdh-γ cluster-deficient mice, γC4fl-only mice were viable and fertile. Furthermore, we show that the γC4 constant region (γCR) contributes to the regulation of Purkinje cell dendritic architecture and self-avoidance. Together, these findings indicate that γCR-containing γC4 is required for neuronal survival and dendritic patterning, supporting γC4 as a principal functional isoform within the Pcdh-γ gene cluster.</p>

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Protocadherin γC4 regulates neuronal survival and dendritic self-avoidance

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月7日

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  • Ryuon Higuchi,
  • Masaki Tatara,
  • Satoko Horino,
  • Shota Katori,
  • Makoto Sanbo,
  • Masumi Hirabayashi,
  • Masahiko Watanabe,
  • Ayumu Konno,
  • Hirokazu Hirai,
  • Yoshichika Yoshioka,
  • Takahiro Hirabayashi,
  • Toshihiro Kobayashi,
  • Ryosuke Kaneko,
  • Takeshi Yagi

摘要

Animal models are indispensable for linking human genetic findings to disease mechanisms. Mutations in protocadherin gamma C4 (γC4), one of the 22 isoforms encoded by the protocadherin-γ (Pcdh-γ) gene cluster, cause a human neurodevelopmental syndrome with progressive microcephaly, seizures, and intellectual disability. Here, we established a γC4 mutant mouse model that exhibits motor dysfunction, seizures, reduced brain size, and increased embryonic neuronal apoptosis. Using DOMINO (Double Mutation-Induced Open Reading Frame Switch), a two-step CRISPR/Cas9-based genome-editing strategy, we also generated γC4fl-only mice that retain full-length γC4 while truncating the other 21 Pcdh-γ isoforms. Unlike Pcdh-γ cluster-deficient mice, γC4fl-only mice were viable and fertile. Furthermore, we show that the γC4 constant region (γCR) contributes to the regulation of Purkinje cell dendritic architecture and self-avoidance. Together, these findings indicate that γCR-containing γC4 is required for neuronal survival and dendritic patterning, supporting γC4 as a principal functional isoform within the Pcdh-γ gene cluster.